Garima Singh1, Bradley J Segura2, Michael K Georgieff1, Tate Gisslen3. 1. Division of Neonatology, Department of Pediatrics, University of Minnesota, East Building MB630, 2450 Riverside Avenue, Minneapolis, MN, 55454, USA. 2. Division of Pediatric Surgery, Department of Surgery, University of Minnesota, East Building MB630, 2450 Riverside Avenue, Minneapolis, MN, 55454, USA. 3. Division of Neonatology, Department of Pediatrics, University of Minnesota, East Building MB630, 2450 Riverside Avenue, Minneapolis, MN, 55454, USA. tgisslen@umn.edu.
Abstract
BACKGROUND: Infants born preterm due to chorioamnionitis are frequently affected by a fetal inflammatory response syndrome (FIRS) and then by subsequent postnatal infections. FIRS and postnatal systemic inflammatory events independently contribute to poor neurocognitive outcomes of preterm infants. Developmental integrity of the hippocampus is crucial for intact neurocognitive outcomes in preterms and hippocampally dependent behaviors are particularly vulnerable to preterm systemic inflammation. How FIRS modulates the hippocampal immune response to acute postnatal inflammatory events is not well understood. METHODS: Prenatal LPS exposed (FIRS) and control neonatal rats received i.p. LPS or saline at postnatal day (P) 5. On P7, immune response was evaluated in the hippocampus of four treatment groups by measuring gene expression of inflammatory mediators and cytosolic and nuclear NFκB pathway proteins. Microglial activation was determined by CD11b+ and Iba1+ immunohistochemistry (IHC) and inflammatory gene expression of isolated microglia. Astrocyte reactivity was measured using Gfap+ IHC. RESULTS: Postnatal LPS resulted in a robust hippocampal inflammatory response. In contrast, FIRS induced by prenatal LPS attenuated the response to postnatal LPS exposure, evidenced by decreased gene expression of inflammatory mediators, decreased nuclear NFκB p65 protein, and fewer activated CD11b+ and Iba1+ microglia. Isolated microglia demonstrated inflammatory gene upregulation to postnatal LPS without evidence of immune tolerance by prenatal LPS. CONCLUSION: Prenatal LPS exposure induced immune tolerance to subsequent postnatal LPS exposure in the hippocampus. Microglia demonstrate a robust inflammatory response to postnatal LPS, but only a partial immune tolerance response.
BACKGROUND:Infants born preterm due to chorioamnionitis are frequently affected by a fetal inflammatory response syndrome (FIRS) and then by subsequent postnatal infections. FIRS and postnatal systemic inflammatory events independently contribute to poor neurocognitive outcomes of preterm infants. Developmental integrity of the hippocampus is crucial for intact neurocognitive outcomes in preterms and hippocampally dependent behaviors are particularly vulnerable to preterm systemic inflammation. How FIRS modulates the hippocampal immune response to acute postnatal inflammatory events is not well understood. METHODS: Prenatal LPS exposed (FIRS) and control neonatal rats received i.p. LPS or saline at postnatal day (P) 5. On P7, immune response was evaluated in the hippocampus of four treatment groups by measuring gene expression of inflammatory mediators and cytosolic and nuclear NFκB pathway proteins. Microglial activation was determined by CD11b+ and Iba1+ immunohistochemistry (IHC) and inflammatory gene expression of isolated microglia. Astrocyte reactivity was measured using Gfap+ IHC. RESULTS: Postnatal LPS resulted in a robust hippocampal inflammatory response. In contrast, FIRS induced by prenatal LPS attenuated the response to postnatal LPS exposure, evidenced by decreased gene expression of inflammatory mediators, decreased nuclear NFκB p65 protein, and fewer activated CD11b+ and Iba1+ microglia. Isolated microglia demonstrated inflammatory gene upregulation to postnatal LPS without evidence of immune tolerance by prenatal LPS. CONCLUSION: Prenatal LPS exposure induced immune tolerance to subsequent postnatal LPS exposure in the hippocampus. Microglia demonstrate a robust inflammatory response to postnatal LPS, but only a partial immune tolerance response.
Authors: Colm P Travers; Waldemar A Carlo; Scott A McDonald; Abhik Das; Edward F Bell; Namasivayam Ambalavanan; Alan H Jobe; Ronald N Goldberg; Carl T D'Angio; Barbara J Stoll; Seetha Shankaran; Abbot R Laptook; Barbara Schmidt; Michele C Walsh; Pablo J Sánchez; M Bethany Ball; Ellen C Hale; Nancy S Newman; Rosemary D Higgins Journal: Am J Obstet Gynecol Date: 2017-11-11 Impact factor: 8.661
Authors: Miriam H Beauchamp; Deanne K Thompson; Kelly Howard; Lex W Doyle; Gary F Egan; Terrie E Inder; Peter J Anderson Journal: Brain Date: 2008-09-17 Impact factor: 13.501
Authors: Jennifer M Strahle; Regina L Triplett; Dimitrios Alexopoulos; Tara A Smyser; Cynthia E Rogers; David D Limbrick; Christopher D Smyser Journal: Neuroimage Clin Date: 2019-03-18 Impact factor: 4.881
Authors: Athina Pappas; Douglas E Kendrick; Seetha Shankaran; Barbara J Stoll; Edward F Bell; Abbott R Laptook; Michele C Walsh; Abhik Das; Ellen C Hale; Nancy S Newman; Rosemary D Higgins Journal: JAMA Pediatr Date: 2014-02 Impact factor: 16.193
Authors: Alice M Graham; Olivia Doyle; Ellen L Tilden; Elinor L Sullivan; Hanna C Gustafsson; Mollie Marr; Madeleine Allen; Kristen L Mackiewicz Seghete Journal: Biol Psychiatry Cogn Neurosci Neuroimaging Date: 2021-10-27